In a method of preparing an antithrombogenic medical material having a heparinized collagen as an antithrombogenic component, there is provided a method comprising the steps of fixing a protamine to a collagen through a polyepoxy compound, and heparinizing the collagen by fixing heparin to the protamine.

Patent
   4806595
Priority
Aug 12 1985
Filed
Aug 01 1986
Issued
Feb 21 1989
Expiry
Aug 01 2006
Assg.orig
Entity
Small
119
6
all paid
1. A method of preparing an antithrombogenic medical material comprising a heparinized collagen as an antithrombogenic component, which comprises the steps of fixing a protamine to a collagen through a polyepoxy compound, and heparinizing said collagen by fixing heparin to said protamine.
2. A method according to claim 1, wherein the protamine is at least one member selected from the group consisting of protamine sulfate and protamine hydrochloride.
3. A method according to claim 1, wherein the polyepoxy compound is at least one member selected from the group consisting of a glycol diglycidyl ether, a polyol polyglycidyl ether, and a dicarboxylic acid diglycidyl ester.
4. A method according to claim 3, wherein the polyepoxy compound is polyethylene glycol diglycidyl ether.
5. A method according to claim 1, wherein the antithrombogenic medical material is a composite of a heparinized collagen and a synthetic polymer.
6. A method according to claim 5, wherein the synthetic polymer material is one member selected from the group consisting of a product prepared by weaving or knitting polyester fibers in the form of a tube, and a plastic molded article.
7. A method according to claim 1, wherein a substrate is subjected to a coating or impregnating treatment with a solution which contains a collagen and a protamine, and said substrate is subsequently immersed in an aqueous solution of a polyepoxy compound, and then immersed in an aqueous heparin solution.
8. A method according to claim 1, wherein a substrate is subjected to a coating or impregnating treatment with a solution containing a collagen, a protamine and a polyepoxy compound, and said substrate is further immersed in an aqueous heparin solution.
9. A method according to claim 1, wherein a substrate is subjected to a coating or impregnating treatment with a solution containing a collagen, a protamine and heparin, and said substrate is further immersed in an aqueous solution of a polyepoxy compound.
10. A method according to claim 1, wherein a substrate is subjected to a coating or impregnating treatment with a solution containing a collagen, a protamine, a polyepoxy compound and heparin, and said substrate is allowed to stand until the fixation of said protamine to said collagen through said polyepoxy compound is completed, and said substrate is subsequently dried.
11. A method according to claim 7, wherein at least one mucopolysaccharide selected from the group consisting of hyaluronic acid, chondroitin sulfate and dermatan sulfate is added to said solution which contains a collagen and a protamine.
12. A method according to claim 8, wherein at least one mucopolysaccharide selected from the group consisting of hyaluronic acid, chondroitin sulfate and dermatan sulfate is added to said solution which contains a collagen, a protamine and a polyepoxy compound.
13. A method according to claim 9, wherein at least one mucopolysaccharide selected from the group consisting of hyaluronic acid, chondroitin sulfate and ermatan sulfate is added to said solution which contains a collagen, a protamine and heparin.
14. A method according to claim 7 or 9, wherein at least one mucopolysaccharide selected from the group consisting of hyaluronic acid, chondroitin sulfate and dermatan sulfate is added to said solution which contains a polyepoxy compound.
15. A method according to claim 7 or 8, wherein at least one mucopolysaccharide selected from the group consisting of hyaluronic acid, chondroitin sulfate and dermatan sulfate is added to said solution which contains heparin.
16. A method according to claim 10, wherein at least one mucopolysaccharide selected from the group consisting of hyaluronic acid, chondroitin sulfate and dermatan sulfate is added to said solution which contains a collagen, a protamine, a polyepoxy compound and heparin.

1. Field of the Invention

The present invention relates to a method of preparing an antithrombogenic medical material

2. Description of the Prior Art

Many medical materials used in the treatment of cardiovascular diseases are required to possess antithrombogenic properties. For instance, in the case of artificial blood-vessels, artificial valves, artificial hearts, and parts of artificial lung devices, if the surfaces coming into contact with blood possess blood coagulating properties, serious problems such as thrombosis may arise. In order to alleviate such problems, a variety of antithrombogenic medical materials consisting of synthetic polymer materials such as a polyurethane have been developed so far. These materials, however, do not always possess sufficient compatibility with endothelial cells and other cells of the living tissues, and therefore with these materials it was difficult to obtain satisfactory antithrombogenic properties.

Collagen is a protein, which is present in connective tissues and basement membranes of animal and is highly compatible with the cells Since collagen has no antithrombogenic property in itself, it is necessary to provide collagen with antithrombogenic properties in order to make the collagen usable as a medical material coming into contact with blood A simple and safe way of providing collagen with antithrombogenic properties is to combine heparin with the collagen through a protamine, in which the protamine is fixed to the collagen through a cross-linking agent For instance, Japanese Patent Application Laid Open No. 58-180162 discloses an antithrombogenic medical material consisting of a heparinized collagen in which heparin is attached to a protamine which is fixed to a collagen of animal origin through glutaraldehyde as a cross-linking agent.

The heparin in the heparinized collagen forms an ionic-bond with protamine and is released slowly in the living body to prevent blood from coagulating. It is further noted that since endothelial cells grow on the collagen base, antithrombogenic properties are maintained by the endothelial cells after the heparin is entirely released

Since, however, glutaraldehyde is used as a cross-linking agent for fixing a protamine to the collagen, the resulting heparinized collagen will have a decreased flexibility and form constrictions or cracks when it is bent to a small radius of curvature. It is also likely that the glutaraldehyde discolors the heparinized collagen to brown, and that the glutaraldehyde is polymerized and released slowly as a polymer under some conditions in the living body, which may cause toxicity for a long period of time.

It is therefore an object of the present invention to provide a method of preparing an antithrombogenic medical material that causes no toxicity and discoloration, and possesses a superior histocompatibility and superior antithrombogenic properties as well as superior physical characteristics, particularly, flexibility.

The above object is attained, according to the present invention, by a method of preparing an antithrombogenic medical material comprising a heparinized collagen as an antithrombogenic component, which comprises the steps of fixing a protamine to a collagen through a polyepoxy compound, and heparinizing the collagen by fixing heparin to the protamine.

Collagens used in the present invention may be, for example, an insoluble collagen, a soluble collagen, an atelocollagen prepared by removing telopeptides on the collagen molecule terminus using protease other than collagenase, a chemically modified collagen obtained by succinylation or esterification of above-described collagens, a collagen derivative such as gelatin, a polypeptide obtained by hydrolysis of collagen, and a natural collagen present in natural tissues (ureter, blood-vessel, pericardium, etc).

Protamines used in the present invention, which are basic nucleoproteins, can be any one collected and purified from any animal, and may contain histones. However, protamines in the form of a salt-like combination with an inorganic salt or an organic salt are preferred, and, in particular, protamine sulfate or protamine hydrochloride is preferred.

Polyepoxy compounds used in the present invention may be, for example, glycol diglycidyl ether, polyol polyglycidyl ether, dicarboxylic acid diglycidylester and so on; in which a polyethylene glycol diglycidyl ether represented by the following formula (I): ##STR1## is particularly preferred because it can provide the heparinized collagen with both flexibility and hydrophilic properties.

Antithrombogenic medical materials prepared by the method according to the present invention may be composites of heparinized collagens and synthetic polymer materials. The synthetic polymer materials may be products prepared by weavng or knitting polyester fibers in the form of a tube, a plastic (for example, polycarbonate) molded article as in the circuit of an artificial lung device, and so on.

The heparinized collagens as an antithrombogenic component in the present invention may be prepared as follows.

In case of using an insoluble collagen as the collagen, the insoluble collagen is immersed in a 0.1% to 20% aqueous protamine and subsequently immersed in a 0.1% to 30%, preferably 1% to 10% aqueous solution of polyepoxy compound to fix the protamine to the collagen. The protamine-fixed collagen is then subjected to heparinization by immersing it in a 0.01% to 10%, preferably 0.1% to 2% aqueous heparin. In the above immersion treatments using each of the above-described aqueous solutions, the temperature may be in the range of from 5°C to 90°C, preferably from 10°C to 35°C, and the duration of immerison may be in the range of from 10 minutes to 24 hours, preferably from 30 minutes to 8 hours.

In an alternative embodiment in which a soluble collagen is used as the collagen, a heparinized collagen is obtained by the process in which a substrate such as a synthetic polymer material and the like is subjected to coating or impregnating treatment with a solution containing the soluble collagen and a protamine, and the substrate is subsequently immersed in an aqueous solution of a polyepoxy compound, and further immersed in a heparin aqueous solution.

In another embodiment, a heparinized collagen is obtained by the process in which a substrate such as a synthetic polymer material is subjected to a coating or impregnating treatment with a solution containing a soluble collagen, a protamine and a polyepoxy compound, and the substrate so treated is further immersed in an aqueous heparin.

In a further embodiment, a heparinized collagen is obtained by the process in which a substrate such as a synthetic polymer material is subjected to a coating or impregnating treatment with a solution containing a soluble collagen, a protamine, and heparin, and the substrate so treated is further immersed in an aqueous solution of a polyepoxy compound.

In a still further embodiment, a heparinized collagen is obtained by the process in which a substrate such as a synthetic polymer material is subjected to a coating or impregnating treatment with a solution containing a soluble collagen, a protamine, a polyepoxy compound and heparin and the substrate so treated is allowed to stand until the fixation of the protamine to the collagen through the polyepoxy compound is completed, and the substrate is subsequently dried

In the foregoing processes, an insoluble collagen can be used in the form of a dispersion instead of the soluble collagen.

In the description of the foregoing heparinization, the solutions are implicitly aqueous solutions where the solvent consists only of water. It is to be noted, however, that aqueous solutions containing inorganic salts or organic substances, organic solvents or mixtures of these solvents can likewise be used.

A mucopolysaccharide such as hyaluronic acid, chondroitin sulfate, or dermatan sulfate can be added to any of the solutions in which collagen is present, which solutions are used in the coating or impregnating treatment of a substrate such as a synthetic polymer material, whereby the resulting heparinized collagen can be provided with an increased histocompatibility and hydrophilic properties.

According to the present invention, it is possible to obtain an antithrombogenic medical material comprising a heparinized collagen having both superior antithrombogenic properties and high flexibility.

The present invention will be understood more readily by reference to the following Examples; however, the Examples are intended to merely illustrate the present invention and are not to be construed whatsoever to limit the scope of the present invention.

In the following examples, polyethylene glycol diglycidyl ether used is Denacol EX-861 (Tradename of Nagase Sangyo K.K.) (n≈22 in the above formula (I)).

The carotid (inner diameter=3 mm; length=10 cm) of an adult dog was immersed in a 0.01% aqueous ficin (pH 7.4) at 25°C for 24 hours to remove proteins other than collagen, and the carotid was then washed well with water. With one end of the carotid closed, the hollow portion of the carotid was filled with a 10% aqueous protamine sulfate (pH 5.0) and the carotid was allowed to stand at room temperature for one hour while air pressure of 100 mmHg was applied thereto After the excess of the solution was removed, the carotid was filled with a 10% aqueous polyethylene glycol diglycidyl ether (pH 8.0) and allowed to stand for one hour in the same xanner described above. Then the excess of the solution was removed. After the above treatments were repeated again, the carotid was washed well with water and was then immersed in a 1% aqueous heparin (pH 6.0) at room temperature for one hour. The carotid, after washed with water, was stored in a 70% aqueous ethanol to provide an artificial blood-vessel. No cracks and constrictions were observed in the artificial blood-vessel when it was bent by hand to a small radius of curvature.

A tube (inner diameter=3 mm; length=10 cm) for an artificial blood-vessel was prepared by knitting polyester fibers. One end of the tube was closed with a stopper, and the hollow of the tube was filled with a mixture of 10 ml of a 1% aqueous atelocollagen (pH 3), 5 ml of a 10% aqueous protamine sulfate (pH 5) and 3 ml of a 0.1% aqueous hyaluronic acid (pH 7). The tube was impregnated with the mixture by applying air pressure of 100 mmHg. After the excess of the solution was removed, a 0.1N aqueous sodium hydroxide with 10% polyethylene glycol diglycidyl ether concentration and 10% NaCl concentration was poured into the tube, and the tube was allowed to stand at room temperature for two hours. The tube was washed well with water and was immersed in a 1% aqueous heparin for one hour, followed by washing well with water. The tube was then immersed in a 5% aqueous glycerin for two hours and freeze-dried to provide an artificial blood-vessel. The resulting artificial blood-vessel was found to have the same satisfactory flexibility as obtained in Example 1.

Each of the artificial blood-vessels prepared in Exmaples 1 and 2 was implanted in the femoral aorta of an adult dog, and no thrombus was observed at all about three months threreafter, showing a 100% open rate.

In 90 g of water were dissolved 1 g of protamine sulfate, 0.1 g of heparin, and 10 g of a reagent-grade gelatin at 50°C The resulting solution was coated on the inner surface of an artificial lung, and a 0.1N aqueous sodium hydroxide with 10% polyethylene glycol diglycidyl ether concentration and 10% NaCl concentration was poured into the artificial lung, which was then allowed to stand at 50°C for two hours, washed well with water, and then air-dried.

In the resulting artificial lung applied to the box part connecting to the hollow fiber in the circuit of an artificial lung device, no thrombus iormation was observed at all for about 5 hours, showing superior antithrombogenic properties compared to those of conventional artificial lungs.

Miyata, Teruo, Noishiki, Yasuharu, Kodaira, Kazuhiko, Furuse, Masayasu

Patent Priority Assignee Title
10611822, Jul 28 2011 HARBOR MEDTECH, INC. Crosslinked human or animal tissue products and their methods of manufacture and use
10844110, May 04 2004 Novo Nordisk Healthcare AG O-linked glycoforms of polypeptides and method to manufacture them
10874714, Oct 29 2004 89BIO LTD Method of treating fibroblast growth factor 21 (FGF-21) deficiency
10940167, Feb 10 2012 CVDevices, LLC Methods and uses of biological tissues for various stent and other medical applications
10993805, Feb 26 2008 JenaValve Technology, Inc. Stent for the positioning and anchoring of a valvular prosthesis in an implantation site in the heart of a patient
11065138, May 13 2016 JENAVALVE TECHNOLOGY, INC Heart valve prosthesis delivery system and method for delivery of heart valve prosthesis with introducer sheath and loading system
11154398, Feb 26 2008 JenaValve Technology. Inc. Stent for the positioning and anchoring of a valvular prosthesis in an implantation site in the heart of a patient
11185405, Aug 30 2013 JenaValve Technology, Inc. Radially collapsible frame for a prosthetic valve and method for manufacturing such a frame
11197754, Jan 27 2017 JenaValve Technology, Inc. Heart valve mimicry
11337800, May 01 2015 JenaValve Technology, Inc. Device and method with reduced pacemaker rate in heart valve replacement
11357624, Apr 13 2007 JenaValve Technology, Inc. Medical device for treating a heart valve insufficiency
11406495, Feb 11 2013 Cook Medical Technologies LLC Expandable support frame and medical device
11517431, Jan 20 2005 JenaValve Technology, Inc. Catheter system for implantation of prosthetic heart valves
11564794, Feb 26 2008 JenaValve Technology, Inc. Stent for the positioning and anchoring of a valvular prosthesis in an implantation site in the heart of a patient
11589981, May 25 2010 JenaValve Technology, Inc. Prosthetic heart valve and transcatheter delivered endoprosthesis comprising a prosthetic heart valve and a stent
12065480, Jul 28 2011 HARBOR MEDTECH, INC. Crosslinked human or animal tissue products and their methods of manufacture and use
12102731, May 01 2020 HARBOR MEDTECH, INC Port-accessible multidirectional reinforced minimally invasive collagen device for soft tissue repair
12121461, Mar 20 2015 JENAVALVE TECHNOLOGY, INC Heart valve prosthesis delivery system and method for delivery of heart valve prosthesis with introducer sheath
12171658, Nov 09 2022 JenaValve Technology, Inc. Catheter system for sequential deployment of an expandable implant
4940751, Oct 23 1987 Essilor International (Compagnie Generale d'Optique) Wettable silicon elastomer for the manufacture of contact lenses
4987184, Nov 10 1987 Bayer AG Mixtures of polycarbonates with siloxane-containing graft polymers
5071973, Nov 20 1986 Process for preparing of non-thrombogenic substrates
5171261, Apr 17 1989 KOKEN CO , LTD Vascular prosthesis, manufacturing method of the same, and substrate for vascular prothesis
5182317, Jul 05 1988 INNERDYNE, INC Multifunctional thrombo-resistant coatings and methods of manufacture
5248766, Aug 17 1990 Baxter International Inc. Oxirane-modified hemoglobin based composition
5262451, Jun 08 1988 BIOSURFACE ENGINEERING TECHNOLOGIES, INC Multifunctional thrombo-resistant coatings and methods of manufacture
5338770, Jun 08 1988 BIO SURFACE ENGINEERING TECHNOLOGIES, INC Gas permeable thrombo-resistant coatings and methods of manufacture
5342693, Jun 08 1988 BIOSURFACE ENGINEERING TECHNOLOGIES, INC Multifunctional thrombo-resistant coating and methods of manufacture
5376110, Feb 14 1991 Edwards Lifesciences Corporation Method of manufacturing pliable biological grafts materials
5383927, May 07 1992 INTERVASCULAR, INC Non-thromogenic vascular prosthesis
5387236, Apr 17 1989 Koken Co., Ltd. Vascular prosthesis, manufacturing method of the same, and substrate for vascular prosthesis
5415619, Dec 13 1989 Korea Research Institute of Chemical Tech. Method of manufacturing a vascular graft impregnated with polysaccharide derivatives
5532311, Feb 01 1995 Terumo Cardiovascular Systems Corporation Process for modifying surfaces
5583213, May 12 1995 Terumo Cardiovascular Systems Corporation Process to activate sulfated polysaccharides
5735897, Oct 19 1993 Boston Scientific Scimed, Inc Intravascular stent pump
5880242, Mar 04 1996 Edwards Lifesciences Corporation Nonpolymeric epoxy compounds for cross linking biological tissue and bioprosthetic grafts prepared thereby
5891196, Apr 16 1997 Edwards Lifesciences Corporation Method for actively binding heparin to crosslinked biological tissues
5986168, Apr 25 1995 Nicem, Ltd. Prosthesis containing bioabsorbable materials insolubilized without chemical reagents and method of making the same
6106555, Dec 15 1998 GRANDHOPE BIOTECH HONG KONG CO , LIMITED Method for tissue fixation
6117979, Aug 18 1997 JARO, MICHAEL J Process for making a bioprosthetic device and implants produced therefrom
6146771, Jul 01 1997 Terumo Cardiovascular Systems Corporation Process for modifying surfaces using the reaction product of a water-insoluble polymer and a polyalkylene imine
6166184, Aug 18 1997 Medtronic, Inc Process for making a bioprosthetic device
6197289, Jul 01 1997 Terumo Cardiovascular Systems Corporation Removal of biologically active agents
6231614, Dec 15 1998 GRANDHOPE BIOTECH HONG KONG CO , LIMITED Method for tissue fixation
6506398, Apr 28 2000 Device for treating diabetes and methods thereof
6506437, Oct 17 2000 Advanced Cardiovascular Systems, Inc. Methods of coating an implantable device having depots formed in a surface thereof
6521284, Nov 03 1999 LifeShield Sciences LLC Process for impregnating a porous material with a cross-linkable composition
6545042, Nov 05 1996 GP Medical Acellular biological material chemically treated with genipin
6624138, Nov 05 1996 GP Medical Drug-loaded biological material chemically treated with genipin
6797311, Nov 03 1999 LifeShield Sciences LLC Process for impregnating a porous material with a cross-linkable composition
6998418, Nov 05 1996 GP MEDICAL, INC Acellular biological material chemically treated with genipin
7060684, Dec 16 2002 Device for treating diabetes and methods thereof
7101857, Nov 05 1996 GP MEDICAL, INC Crosslinkable biological material and medical uses
7125843, Oct 10 2001 Novo Nordisk A S Glycoconjugates including more than one peptide
7157277, Oct 10 2001 Novo Nordisk A S Factor VIII remodeling and glycoconjugation of Factor VIII
7159593, Apr 17 2003 3F THERAPEUTICS, INC Methods for reduction of pressure effects of cardiac tricuspid valve regurgitation
7173003, Oct 10 2001 Novo Nordisk A S Granulocyte colony stimulating factor: remodeling and glycoconjugation of G-CSF
7179617, Oct 10 2001 Novo Nordisk A S Factor IX: remolding and glycoconjugation of Factor IX
7214660, Oct 10 2001 Novo Nordisk A S Erythropoietin: remodeling and glycoconjugation of erythropoietin
7226903, Oct 10 2001 Novo Nordisk A S Interferon beta: remodeling and glycoconjugation of interferon beta
7265084, Oct 10 2001 Novo Nordisk A S Glycopegylation methods and proteins/peptides produced by the methods
7265085, Oct 10 2001 Novo Nordisk A S Glycoconjugation methods and proteins/peptides produced by the methods
7276475, Oct 10 2001 Novo Nordisk A S Remodeling and glycoconjugation of peptides
7282220, Nov 05 1996 GP Medical Genipin-crosslinked gelatin microspheres as drug carrier
7297511, Oct 10 2001 Novo Nordisk A S Interferon alpha: remodeling and glycoconjugation of interferon alpha
7351421, Nov 05 1996 GP MEDICAL, INC Drug-eluting stent having collagen drug carrier chemically treated with genipin
7399613, Oct 10 2001 Novo Nordisk A S Sialic acid nucleotide sugars
7405198, Nov 24 2003 Novo Nordisk A S Glycopegylated erythropoietin
7416858, Oct 10 2001 Novo Nordisk A S Pharmaceutical compositions of glycoconjugates
7439043, Oct 10 2001 Novo Nordisk A S Galactosyl nucleotide sugars
7473680, Nov 28 2001 Novo Nordisk A S Remodeling and glycoconjugation of peptides
7530995, Apr 17 2003 MEDTRONIC 3F THERAPEUTICS, INC Device for reduction of pressure effects of cardiac tricuspid valve regurgitation
7691603, Apr 09 2003 Novo Nordisk A S Intracellular formation of peptide conjugates
7696163, Oct 08 2003 Biogenerix AG; Novo Nordisk A S Erythropoietin: remodeling and glycoconjugation of erythropoietin
7795210, Oct 10 2001 Novo Nordisk A S Protein remodeling methods and proteins/peptides produced by the methods
7803777, Mar 14 2003 ratiopharm GmbH Branched water-soluble polymers and their conjugates
7842661, Nov 24 2003 Novo Nordisk A S Glycopegylated erythropoietin formulations
7846199, Nov 19 2007 Cook Medical Technologies LLC Remodelable prosthetic valve
7932364, May 09 2003 Biogenerix AG; Novo Nordisk A S Compositions and methods for the preparation of human growth hormone glycosylation mutants
7956032, Dec 03 2003 Neose Technologies, Inc Glycopegylated granulocyte colony stimulating factor
8008252, Oct 10 2001 Novo Nordisk A S Factor VII: remodeling and glycoconjugation of Factor VII
8053410, Jun 21 2002 Novo Nordisk Healthcare AG Pegylated factor VII glycoforms
8063015, Apr 09 2004 Novo Nordisk A/S Glycopegylation methods and proteins/peptides produced by the methods
8076292, Oct 10 2001 Novo Nordisk A S Factor VIII: remodeling and glycoconjugation of factor VIII
8197534, Mar 31 2005 Cook Medical Technologies LLC Valve device with inflatable chamber
8207112, Aug 29 2007 ratiopharm GmbH Liquid formulation of G-CSF conjugate
8216299, Apr 01 2004 Cook Medical Technologies LLC Method to retract a body vessel wall with remodelable material
8247381, Mar 14 2003 ratiopharm GmbH Branched water-soluble polymers and their conjugates
8268967, Sep 10 2004 Biogenerix AG; Novo Nordisk A S Glycopegylated interferon α
8361961, Jan 08 2004 ratiopharm GmbH O-linked glycosylation of peptides
8404809, May 25 2005 Novo Nordisk A/S Glycopegylated factor IX
8414872, Sep 10 2007 LIQUID KERATIN, INC Hair straightening formulations, methods and systems
8597226, Sep 10 1998 JENAVALVE TECHNOLOGY, INC ; JVT RESEARCH & DEVELOPMENT CORPORATION Methods and conduits for flowing blood from a heart chamber to a blood vessel
8632770, Dec 03 2003 Novo Nordisk A/S Glycopegylated factor IX
8633157, Nov 24 2003 Novo Nordisk A S Glycopegylated erythropoietin
8716239, Oct 19 2001 Novo Nordisk A S Granulocyte colony stimulating factor: remodeling and glycoconjugation G-CSF
8716240, Oct 10 2001 Novo Nordisk A S Erythropoietin: remodeling and glycoconjugation of erythropoietin
8758430, Jan 25 2008 JENAVALVE TECHNOLOGY, INC ; JVT RESEARCH & DEVELOPMENT CORPORATION Medical apparatus for the therapeutic treatment of an insufficient cardiac valve
8791066, Jul 13 2004 Novo Nordisk A/S Branched PEG remodeling and glycosylation of glucagon-like peptide-1 [GLP-1]
8791070, Apr 09 2003 Novo Nordisk A/S Glycopegylated factor IX
8841439, Nov 03 2005 Novo Nordisk A/S Nucleotide sugar purification using membranes
8853161, Apr 09 2003 Novo Nordisk A/S Glycopegylation methods and proteins/peptides produced by the methods
8901078, Jul 28 2011 HARBOR MEDTECH, INC Crosslinked human or animal tissue products and their methods of manufacture and use
8911967, Aug 19 2005 Novo Nordisk A/S One pot desialylation and glycopegylation of therapeutic peptides
8916360, Nov 24 2003 Novo Nordisk A S Glycopegylated erythropoietin
8969532, Oct 03 2006 Novo Nordisk A S Methods for the purification of polypeptide conjugates comprising polyalkylene oxide using hydrophobic interaction chromatography
9005625, Jul 25 2003 Biogenerix AG; Novo Nordisk A S Antibody toxin conjugates
9017397, Mar 31 2005 Cook Medical Technologies LLC Valve device with inflatable chamber
9023992, May 04 2004 Novo Nordisk Healthcare AG Hydrophobic interaction chromatography purification of factor VII polypeptides
9029331, Jan 10 2005 Biogenerix AG; Novo Nordisk A S Glycopegylated granulocyte colony stimulating factor
9050304, Apr 03 2007 ratiopharm GmbH Methods of treatment using glycopegylated G-CSF
9150848, Feb 27 2008 Novo Nordisk A/S Conjugated factor VIII molecules
9187532, Jul 21 2006 Novo Nordisk A S Glycosylation of peptides via O-linked glycosylation sequences
9187546, Apr 08 2005 Biogenerix AG; Novo Nordisk A S Compositions and methods for the preparation of protease resistant human growth hormone glycosylation mutants
9200049, Oct 29 2004 89BIO LTD Remodeling and glycopegylation of fibroblast growth factor (FGF)
9220808, Jul 28 2011 HARBOR MEDTECH, INC Crosslinked human or animal tissue products and their methods of manufacture and use
9399084, Jul 28 2011 HARBOR MEDTECH, INC Crosslinked human or animal tissue products and their methods of manufacture and use
9493499, Jun 12 2007 ratiopharm GmbH Process for the production of purified cytidinemonophosphate-sialic acid-polyalkylene oxide (CMP-SA-PEG) as modified nucleotide sugars via anion exchange chromatography
9592320, Jul 28 2011 HARBOR MEDTECH, INC. Crosslinked human or animal tissue products and their methods of manufacture and use
Patent Priority Assignee Title
4001200, Feb 27 1975 QUEST BLOOD SUBSTITUTE, INC , 320 FISHER BUILDING, DETROIT, MI 48202, A CORP OF MI Novel polymerized, cross-linked, stromal-free hemoglobin
4690973, Jul 29 1985 Koken Company Limited Production process of an antithrombogenic and antiadhesive material for medical use
4704131, Apr 19 1982 KOKEN CO, LTD Medical materials
EP92414,
JP58180162,
JP60203264,
/////
Executed onAssignorAssigneeConveyanceFrameReelDoc
Jul 17 1986NOISHIKI, YASUHARUKOKEN CO , LTD ASSIGNMENT OF ASSIGNORS INTEREST 0045860808 pdf
Jul 17 1986KODAIRA, KAZUHIKOKOKEN CO , LTD ASSIGNMENT OF ASSIGNORS INTEREST 0045860808 pdf
Jul 17 1986FURUSE, MASAYASUKOKEN CO , LTD ASSIGNMENT OF ASSIGNORS INTEREST 0045860808 pdf
Jul 17 1986MIYATA, TERUOKOKEN CO , LTD ASSIGNMENT OF ASSIGNORS INTEREST 0045860808 pdf
Aug 01 1986Koken Co., Ltd.(assignment on the face of the patent)
Date Maintenance Fee Events
Aug 06 1992M283: Payment of Maintenance Fee, 4th Yr, Small Entity.
Aug 05 1996M284: Payment of Maintenance Fee, 8th Yr, Small Entity.
Aug 14 2000M285: Payment of Maintenance Fee, 12th Yr, Small Entity.


Date Maintenance Schedule
Feb 21 19924 years fee payment window open
Aug 21 19926 months grace period start (w surcharge)
Feb 21 1993patent expiry (for year 4)
Feb 21 19952 years to revive unintentionally abandoned end. (for year 4)
Feb 21 19968 years fee payment window open
Aug 21 19966 months grace period start (w surcharge)
Feb 21 1997patent expiry (for year 8)
Feb 21 19992 years to revive unintentionally abandoned end. (for year 8)
Feb 21 200012 years fee payment window open
Aug 21 20006 months grace period start (w surcharge)
Feb 21 2001patent expiry (for year 12)
Feb 21 20032 years to revive unintentionally abandoned end. (for year 12)